Ajmalicine synthesis

Incubation of geissoschizine (35) with a cell-free extract from C. roseus 210) in the presence of NADPH caused the accumulation of an isomer of isositsrikine whose structure was established chemically to be the (167 ) isomer 58. None of the 16-epi isomer 95 was detected in the cell-free incubations or in feeding experiments with intact plants. Additionally, Stdck-igt has reviewed enzymatic studies on the formation of strictosidine (33) and cathenamine (76) (277), and Zenk has provided a very elegant summary of the enzymatic synthesis of ajmalicine (39) (272). 

DiCosmo, F., Quesnel, A., Misawa, M. and Tallevi, S. G. 1987. Increased synthesis of ajmalicine and catharanthine by cell suspension cultures of Catharanthus roseus in response to fungal culture-filtrates. Applied Biochemistry and Biotechnology, 14 101-106. 

Overman and co-workers have reported Mannich bis-cyclizations (carboxylate-terminated iV-acyliminium ion bis-cyclizations Scheme 56) and employed these in the total synthesis of (—)-ajmalicine <1995JA9139>. 

A similar vinylogous Mannich reaction has been used by Martin in the total syntheses of the heteroyohimboid alkaloids (—)-ajmalicine and (—)-tetrahydroalstonine <1995JOC3236>. An attempted synthesis of an opioid analgesic 2,4-dibenzyl-3,7-diazabicyclo[3.3.1]nonan-9-one-l,5-dicarboxylate (piperidone) by a double Mannich reaction of oxoglutarate, 2 equiv of phenylacetaldehyde, and methylamine did not give the expected product but instead gave rise to an unexpected [l,6]naphthyridine derivative (Scheme 57) <1998PHA442>. 

In the transcript of a lecture, Zenk has reviewed58 the enzymic synthesis of ajmalicine and its biogenetic intermediates from secologanin and tryptamine in cell clones of Catharanthus roseus. 

The UV-spectrum of mitragynine differs notably from the spectra of the other Mitragyna alkaloids. Whereas the absorption of the latter indicate the presence of oxindole nuclei, the spectrum of mitragynine shows a greater resemblance to that of the ajmalicine group of alkaloids (5). The presence of an indole nucleus is also suspected from its color reactions (2) and confirmed by the isolation of indole derivatives (so far unidentified) and 5-methoxy-9-methylharman (I) from the products of zinc dust distillation (6). The identification by synthesis (51) of this degradation product is of some interest, since the alkaloid itself does not apparently contain an iV-methyl group. Moreover, this was the first demonstration of the occurrence of a 4-hydroxyindole derivative in nature. 

These conclusions have received convincing confirmation in a partial synthesis of mitraphylline and isomitraphylline from ajmalicine (IX)... 

Mitraphylline and rhynchophylline undergo characteristic fragmentation processes on electron impact, hence their mass spectra are markedly different from those of the tetrahydro-/3-carboline alkaloids in general, and of the heteroyohimbine alkaloids (e.g., ajmalicine) in particular. Consequently, the mass spectra of the oxindole alkaloids promise to be very valuable in the structural elucidation of new members of this subgroup the structure of one such base, carapanaubine, a constituent of Aspidosperma carapanauba M. Pichon, has already been elucidated by this method, and the structure deduced has subsequently been confirmed by partial synthesis from isoreserpiline (82). 

On the basis of these conclusions it was perhaps surprising that a nonstereospecific synthesis of a heteroyohimbine should yield predominantly the presumed cis D/E isomer, ( )-ajmalicine, rather than the trans D/E isomer (60). However, later correlations by reliable chemical and physical methods proved beyond doubt that the earlier... 

The stereochemistry of the heteroyohimbanes has largely been elucidated, and a total synthesis of ajmalicine has been achieved. 

Synthesis of [methyl-2H]-labelled ajmalicine, yohimbine, tabersonine and catharanthine... 

Ajmalicine, 19-epi-ajmalicine and tetrahydroalstonine are formed from 4,21-dehydrogeissoschizine via cathenamine (Fig. 2.9). The enzymatic synthesis of these corynanthe-type alkaloids has been investigated using C. roseus cell suspension cultures, and the enzymes involved have been reviewed by De Luca (1993) and Ziegler and Facchini (2008). Ajmalicine can be oxidized by POD to serpentine. This reaction may take in the vacuole. 

Oxidative cyclization. The final step in a synthesis of racemic ajmalicine (2) required oxidative cyclization of (I). This reaction was carried out in 2.5% aqueous acetic acid with an excess of 1 1 mercuric acelale-ethylenediaminetetraacetic acid disodium salt (EDTA, I, 373-374) followed by sodium borohydride reduction of iminium intermediates. 

C. roseus is, therefore, an amazing chemical factory, which produces more than 100 different monoterpenoid indole alkaloids, many of them possessing notable pharmacological activity [158-159]. The main alkaloids present in C. roseus plants are catharanthine, vindoline and a-3 ,4 -anhydrovinblastine. Ajmalicine and serpentine are also present in significant amounts in the plant [160-165]. Class III plant peroxidases have been involved in the synthesis of many of these monoterpenoid indole alkaloids. 

The attempts by the same investigators to realize the synthesis of ajmalicine from corynantheine derivatives, previously reported" in brief, have now been published in detail " thus, while oxymercuration of demethylcorynantheine (115) followed by NaBHt reduction gave small quantities of ajmalicine (80) and 19-epiajmalicine, the major product was the IS-abeo (17 16) yohimbane derivative (116). 

In continuation of his biomimetic syntheses of heteroyohimbine alkaloids Brown" has succeeded in converting secologanin tetra-acetate (117) into elenolic acid (118), and in completing the synthesis of ajmalicine (80) essentially by the route published" earlier (Scheme 14). Contrary to the previous workers, who apparently isolated only ajmalicine. Brown eta/." obtained ajmalicine (80), 19-epiajmalicine (119) and tetrahydroalstonine (120). Since one of the lactams (121) afforded only 19-epiajmalicine (119) and in the general reaction sequence the proportion of (80), (119), and (120) in the final product depended on the length of time allowed for Schiff base formation rather than on the ratio of isomers present in the methyl elenolate [ester of (118)], it is apparent that interconversion of the imines (122) via the equilibria shown in Scheme 14 is responsible for the non-stereospecificity of the synthesis. 

The stereochemical assignments for the cyclization of 25.1 were based on conversion into synthetic intermediates for the synthesis of (— )-ajmalicine (25.6), (— )-tetrahydroalstonine (25.7), and ( — )-(10K)-hydroxydihydroquinine (25.8). No details of the stereochemical assignment of 25.5 were reported. These results can be rationalized by transition state 25.9, which allows for association of the donor and acceptor portions of the substrate. Attack occurs from the face of the enamine opposite to the phenyl group. As in the intermolecular reactions of similar imines, these reactions are probably under kinetic control. 

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